Overview
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to maximum tolerated background PAH therapy on time to first event of all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥24 hours, in participants with WHO FC III PAH or WHO FC IV PAH at high risk of mortality.
Participants with symptomatic PAH (WHO FC III or FC IV at high risk of mortality) who present with idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin-induced, post-shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defect. Participants must have a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 risk score of ≥9 and be on maximum tolerated combination background PAH therapy.
Principal investigator
Eligibility criteria
Inclusion Criteria:
* Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes:
* Idiopathic PAH
* Heritable PAH
* Drug/toxin-induced PAH
* PAH associated with connective tissue diseases (CTD)
* PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
* Symptomatic PAH classified as WHO functional class (FC) III or IV
* Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9
* Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum pulmonary vascular resistance (PVR) of ≥5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤15 mmHg
* Clinically stable and on stable doses of maximum tolerated (per investigator's judgment) double or triple background PAH therapies for at least 30 days prior to screening
* Females of childbearing potential must:
* Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
* If sexually active with a male partner, have used, and agree to use highly effective contraception without interruption per protocol; for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
* Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
* Male participants must:
* Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
* Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
* Ability to adhere to study visit schedule and understand and comply with all protocol requirements
* Ability to understand and provide written informed consent
Exclusion Criteria:
* Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
* Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
* Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
* Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
* Baseline platelet count \<50,000/mm3 (\<50.0 x 109/L) at screening
* Baseline systolic blood pressure \<85 mmHg at screening
* Pregnant or breastfeeding women
* Serum alanine aminotransferase or aspartate aminotransferase levels or total bilirubin \>3.0×ULN
* Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
* Prior exposure to sotatercept or known allergic reaction to sotatercept, its excipients or luspatercept
* History of pneumonectomy
* Untreated more than mild obstructive sleep apnea
* History of known pericardial constriction
* History of restrictive or congestive cardiomyopathy
* Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) \>500 ms during the screening period
* Personal or family history of long QT syndrome or sudden cardiac death
* Left ventricular ejection fraction \<45% on historical echocardiogram within 1 year prior to the screening visit
* Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the screening visit
* Cerebrovascular accident within 3 months prior to the screening visit
* Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
* Currently on dialysis or anticipated need for dialysis within the next 12 months
* Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes:
* Idiopathic PAH
* Heritable PAH
* Drug/toxin-induced PAH
* PAH associated with connective tissue diseases (CTD)
* PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
* Symptomatic PAH classified as WHO functional class (FC) III or IV
* Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9
* Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum pulmonary vascular resistance (PVR) of ≥5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤15 mmHg
* Clinically stable and on stable doses of maximum tolerated (per investigator's judgment) double or triple background PAH therapies for at least 30 days prior to screening
* Females of childbearing potential must:
* Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
* If sexually active with a male partner, have used, and agree to use highly effective contraception without interruption per protocol; for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
* Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
* Male participants must:
* Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
* Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
* Ability to adhere to study visit schedule and understand and comply with all protocol requirements
* Ability to understand and provide written informed consent
Exclusion Criteria:
* Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
* Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
* Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
* Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
* Baseline platelet count \<50,000/mm3 (\<50.0 x 109/L) at screening
* Baseline systolic blood pressure \<85 mmHg at screening
* Pregnant or breastfeeding women
* Serum alanine aminotransferase or aspartate aminotransferase levels or total bilirubin \>3.0×ULN
* Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
* Prior exposure to sotatercept or known allergic reaction to sotatercept, its excipients or luspatercept
* History of pneumonectomy
* Untreated more than mild obstructive sleep apnea
* History of known pericardial constriction
* History of restrictive or congestive cardiomyopathy
* Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) \>500 ms during the screening period
* Personal or family history of long QT syndrome or sudden cardiac death
* Left ventricular ejection fraction \<45% on historical echocardiogram within 1 year prior to the screening visit
* Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the screening visit
* Cerebrovascular accident within 3 months prior to the screening visit
* Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
* Currently on dialysis or anticipated need for dialysis within the next 12 months
For Referring Providers
Do you have a patient you think would be a good candidate for this trial? Learn more about enrolling your patient.